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Key information relevant to the recruitment process for the
overall study, such as dates of the recruitment period and locations

Patients were recruited from study sites in the United States, Argentina, Peru, Columbia, Chile, and Peru. There were 47 patients from the Latin American countries.

Pre-Assignment Details

Significant events and approaches for the overall study
following participant enrollment, but prior to group assignment

No text entered.

Reporting Groups

Description

Sham Injection/Ranibizumab 0.5 mg

Patients received a sham intravitreal injection monthly for 24 months. Patients who had not discontinued treatment by Month 24 could choose to receive ranibizumab 0.5 mg monthly administered intravitreally for the subsequent 12 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months.

Ranibizumab 0.3 mg

Patients received ranibizumab 0.3 mg monthly administered intravitreally for 36 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months.

Ranibizumab 0.5 mg

Patients received ranibizumab 0.5 mg monthly administered intravitreally for 36 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months.

Participant Flow for 3 periods

Period 1: Core Study

Sham Injection/Ranibizumab 0.5 mg

Ranibizumab 0.3 mg

Ranibizumab 0.5 mg

STARTED

130

125

127

COMPLETED

102

98

98

NOT COMPLETED

28

27

29

Adverse Event

3

1

1

Death

3

5

10

Lost to Follow-up

3

3

3

Physician Decision

1

2

2

Subject non-compliance

5

2

1

Subject needed other treatment

1

3

2

Subject's decision

12

11

10

Period 2: Open-label Extension Through Month 48

Sham Injection/Ranibizumab 0.5 mg

Ranibizumab 0.3 mg

Ranibizumab 0.5 mg

STARTED

88 [1]

83 [1]

84 [1]

COMPLETED

38

42

37

NOT COMPLETED

50

41

47

Adverse Event

0

0

1

Death

1

3

3

Lost to Follow-up

1

2

1

Subject's Decision

5

1

6

Sponsor’s Decision to Terminate Study

41

34

36

Subject Required Other Intervention

2

1

0

[1]

Not all participants who completed the core study entered the optional open-label extension.

Period 3: Open-label Extension Through Month 60

Sham Injection/Ranibizumab 0.5 mg

Ranibizumab 0.3 mg

Ranibizumab 0.5 mg

STARTED

88 [1]

83 [1]

84 [1]

COMPLETED

2

1

2

NOT COMPLETED

86

82

82

Adverse Event

0

0

2

Death

1

7

4

Lost to Follow-up

1

3

1

Subject's Decision

7

1

6

Sponsor’s Decision to Terminate Study

75

70

69

Subject Required Other Intervention

2

1

0

[1]

Not all participants who completed the core study entered the optional open-label extension.

Explanation of how the number of participants for analysis was determined.
Includes whether analysis was per protocol, intention to treat, or another method.
Also provides relevant details such as imputation technique, as appropriate.

The Baseline Characteristics of the patients enrolled in the open-label extension phase (N=88, 83, 84 patients originally randomized to the ranibizumab 0.3 mg, ranibizumab 0.5 mg, and sham injection groups, respectively) were similar to the Baseline Characteristics of the patients enrolled in the core study.

Reporting Groups

Description

Ranibizumab 0.3 mg

Patients randomized to this group received ranibizumab 0.3 mg monthly administered intravitreally for 24 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months.

Ranibizumab 0.5 mg

Patients randomized to this group received ranibizumab 0.5 mg monthly administered intravitreally for 24 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months.

Sham Injection

Patients randomized to this group received a sham intravitreal injection monthly for 24 months.

Resolution of leakage was defined as total area of fluorescein leakage in the central, inner, and outer subfields of the 0 Disc Area. Leakage was assessed in fluorescein angiographic images by the central reading center.

Time Frame

Baseline to Month 24

Population Description

Explanation of how the number of participants for analysis was determined.
Includes whether analysis was per protocol, intention to treat, or another method.
Also provides relevant details such as imputation technique, as appropriate.

Intent-to-treat population: All randomized patients, whether or not treatment was received. Missing data were imputed using the last observation carried forward method.

Reporting Groups

Description

Ranibizumab 0.3 mg

Patients randomized to this group received ranibizumab 0.3 mg monthly administered intravitreally for 24 months.

Ranibizumab 0.5 mg

Patients randomized to this group received ranibizumab 0.5 mg monthly administered intravitreally for 24 months.

Sham Injection

Patients randomized to this group received a sham intravitreal injection monthly for 24 months.

Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:

To manage the type I error rate while testing multiple secondary efficacy endpoints for statistical significance, a type I error management plan was implemented. Secondary endpoints were prioritized and tested using a hierarchical testing procedure.

[5]

Other relevant estimation information:

The percentage for each group and the difference in percentage between groups were estimated using the weighted average of the observed percentages and the differences in observed percentages over the strata using the Cochran-Mantel-Haenszel weights.

Statistical Analysis 2 for Percentage of Patients With Resolution of Leakage at Month 24

Groups [1]

Ranibizumab 0.5 mg vs. Sham Injection

Statistical Test Type [2]

Superiority or Other

Statistical Method [3]

Cochran-Mantel-Haenszel

P Value [4]

<0.0001

Difference in percentage at Month 24 [5]

28.3

95% Confidence Interval

20.2 to 36.4

[1]

Additional details about the analysis, such as null hypothesis and power calculation:

No text entered.

[2]

Details of power calculation, definition of non-inferiority margin, and other key parameters:

No text entered.

[3]

Other relevant method information, such as adjustments or degrees of freedom:

Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:

To manage the type I error rate while testing multiple secondary efficacy endpoints for statistical significance, a type I error management plan was implemented. Secondary endpoints were prioritized and tested using a hierarchical testing procedure.

[5]

Other relevant estimation information:

The percentage for each group and the difference in percentage between groups were estimated using the weighted average of the observed percentages and the differences in observed percentages over the strata using the Cochran-Mantel-Haenszel weights.

9. Secondary:

Mean Number of Macular Laser Treatments From Baseline Through Months 24 and 36 [ Time Frame: Baseline to Month 36 ]